PDGF (platelet-derived growth factor) is known to act as an aggravating factor for cell-proliferative diseases such as arteriosclerosis, vascular reobstruction after percutaneous coronary angioplasty and bypass operation, cancer, glomerulonephritis, glomerulosclerosis, psoriasis and articular rheumatism [Cell, 46, 155-169 (1986); Science, 253, 1129-1132 (1991); Nippon Rinsho (Japanese J. of Clinical Medicine), 50, 3038-3045 (1992); Nephrol Dial Transplant, 10, 787-795 (1995); Kidney International, 43 (Suppl. 39), 86-89 (1993); Journal of Rheumatology, 21, 1507-1511 (1994); Scandinavian Journal of Inmmunology, 27, 285-294 (1988), etc.].
As for quinazoline derivatives which are useful as drugs, N,N-dimethyl-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazine carboxamide is described as a bronchodilator in South African Patent No. 67 06512 (1968). Dimethoxyquinazoline derivatives are described as inhibitors of phosphorylation of epidermal growth factor (EGF) receptor in Japanese Published Unexarnined Patent Application No. 208911/93 and WO 96/09294. Quinoline derivatives having benzodiazepin receptor agonist activity are described in Pharmacology Biochemistry and Behavior, 53, 87-97 (1996) and European Journal of Medicinal Chemistry, 31, 417-425 (1996), and quinoline derivatives which are useful as anti-parasite agents are described in Indian Journal of Chemistry, 26B, 550-555 (1987).
Inhibitors of phosphorylation of PDGF receptor so far known include bismono- and bicyclic aryl compounds and heteroaryl compounds (WO 92/20642), quinoxaline derivatives [Cancer Research, 54, 6106 (1994)], pyrimidine derivatives (Japanese Published Unexamined Patent Application No. 87834/94) and dimethoxyquinoline derivatives [Abstracts of the 16th Annual Meeting of the Pharmaceutical Society of Japan (Kanazawa) (1996), 2, p. 275, 29(C2) 15-2].
Disclosure of the Invention
An object of the present invention is to provide nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which have inhibitory activity on the phosphorylation of kinases, which inhibits the activity of the kinases. Particularly important kinase inhibition according to the invention is of receptor tyrosine kinases including platelet-derived growth factor (PDGF) receptor, Flt3, CSF-1R, epidermal growth factor receptor (EGRF), fibroblast growth factor (FGF), vascular endothelial growth factor receptor (VEGFR) and others. Another class of kinase inhibition according to the invention is inhibitory activity nonreceptor tyrosine Iinases including src and abl, and the like. A third class of kinase inhibition according to the invention is inhibitory activity toward serine/threonine kinases, including such kinases as MAPK, MEK and cyclin dependent kinases (CDKs) that mediate cell prolifetation, AKT and CDK such that mediate cell survival and NIK that regulate inflammatory responses. Tnhibition of such kinases can be used to treat diseases involving cell survival, proliferation and migration, including cardiovascular disease, such as arteriosclerosis and vascular reobstruction, cancer, glomerulosclerosis fibrotic diseases and inflammation, as well as the general treatment of cell-proliferative diseases.
In a preferred embodiment, the present invention provides compounds and pharmaceutically acceptable salts thereof which inhibit or prevent inhibition of phosphorylation of at least one PDGF receptor by at least one tyrosine kinase. Such PDGF receptor kinase inhibition can hinder abnormal cell growth and cell wandering, and thus such compounds are useful for the prevention or treatment of cell-proliferative diseases such as arteriosclerosis, vascular reobstruction, cancer and glomerulosclerosis.
The present invention relates to nitrogen-containing heterocyclic compounds represented by formula I as follows: wherein    R1 is a member selected from the group consisting of:            —CN, —X, —CX3, —R5, —CO2R5, —C(O)R5, —SO2R5, —O—C1-8 alkyl that is straight or branched chained, —O-phenyl, —O-naphthyl, —O-indolyl and —O-isoquinolinyl;            X is a halogen;    R5 is hydrogen or a Cl1-8, alkyl that is straight or branched chained;    R2 and R4 are each independently a member selected from the group consisting of:            —O—CH3, —O—CH2—CH3, —O—CH2—CH═CH2, —O—CH2—C≡CH, —O(CH2)n—SO2—R5, —O—CH2—CH(R6)CH2—R3 and —O(—CH2)n—R3;            R6 is —OH, —X, or a C1-8 alkyl that is straight or branched chained;    n is 2 or 3;    R3 is a member selected from the group consisting of:    —OH, —O—CH3, —O—CH2—CH3, —NH2, —N(—CH3)2, —NH(—CH2-phenyl), —NH(-Phenyl), —CN 
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
Particularly preferred compounds according to formula above are such compounds wherein R1 is a member selected from the group consisting of CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy, and position isomers and homologs thereof, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives of such compounds.
Also, particularly preferred are such compounds wherein R2 and R4 are different and one of R2 and R4 is —O—CH3, and all pharmaceutically acceptable isomers salts, hydrates, solvates and prodrug derivatives of such compounds.
The pharmaceutically acceptable salts of the compounds according to formula (I) include pharmaceutically acceptable acid addition salts, metal salts, animonium salts, organic amine addition salts, amino acid addition salts, etc.
Examples of the pharmaceutically acceptable acid addition salts of the compounds of formula (I) are inorganic acid addition salts such as hydrochloride, sulfate and phosphate, and organic acid addition salts such as acetate, maleate, fumarate, tartrate, citrate and methanesulfonate.
Examples of the pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt. Examples of the pharmaceutically acceptable ammonium salts are ammonium salt and tetramethyl ammonium salt. Examples of the pharmaceutically acceptable organic amine addition salts include heterocyclic amine salts such as morpholine and piperidine salts. Examples of the pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine and phenylalanine.
In a preferred embodiment the invention provides compounds according to formula I(a) and formula I(b) as follows: wherein    R1 is a member selected from the group consisting of:    —CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
In another preferred embodiment the invention provides compounds according to formula (Ic) and formula (Id) as follows: wherein    R1 is a member selected from the group consisting of:    —CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
In still another preferred embodiment the invention provides compounds according to formula I(e) and formula I(f) as follows: wherein    R1 is a member selected from the group consisting of:    —CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
In yet another preferred embodiment the invention provides compounds according to formula I(g) and formula I(h) as follows: wherein    n is 2 or 3; and    R1 is a member selected from the group consisting of:    —CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy;    R3 is a member selected from the group consisting of:    —OH, —O—CH3, —O—CH2—CH3, —NH2, —N(—CH3)2, —NH(—CH2-phenyl), —NH(-Phenyl), —CN and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
The pharmaceutically acceptable salts of the compounds according to formula (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, etc.
The present invention is not limited by the above listed compounds. Analogs of the bicyclic compounds are contemplated.
Further, an especially preferred embodiment of the present invention is a compound selected from the group consisting of:N-(4-indol-5-yloxyphenyl){4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}carboxamide N-(4-indol-4-yloxyphenyl){4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}carboxamide {4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-(4-naphthyloxyphenyl)carboxamide {4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-(4-(2-naphthyloxy)phenyl)carboxamide N-(4-(5-isoquinolyloxy)phenyl){4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}carboxamide {4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-(4-phenoxyphenyl)carboxamide {4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide N-(4-cyanophenyl)(4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl)carboxamide {4-[6-methoxy-7-(2-piperidylethoxy)quinazolin-4-yl]piperazinyl}-N-[4-methylethoxy)phenyl]carboxamide N-(4-cyanophenyl){4-[6-methoxy-7-(2-piperidylethoxy)quinazolin-4-yl]piperazinyl}carboxamide {4-[6-methoxy-7-(3-piperidylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide {4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide N-(4-cyanophenyl){4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]piperazinyl}carboxamide {4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide N-(4-cyanophenyl){4-[6-methoxy-7-(2-(1,2,3,4-tetraazol-2-yl)ethoxy)quinazolin-4-yl]piperazinyl}carboxamide N-(4-cyanophenyl){4-[6-methoxy-7-(2-(1,2,3,4-tetraazolyl)ethoxy)quinazolinyl]piperazinyl}carboxamide {4-[6-methoxy-7-(2-(1,2,3,4-tetraazolyl)ethoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide {4-[6-methoxy-7-(2-(1,2,3,4-tetraazol-2-yl)ethoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide (4-{7-[3-(4,4-difluoropiperidyl)propoxy}-6-methoxyquinazolin-4-yl]piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide {4-[6-methoxy-7-(3-piperazinylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide N-(4-cyanophenyl)(4-{6-methoxy-7-[3-(4-methylpiperazinyl)propoxy]quinazolin-yl}piperazinyl)carboxamide N-(4-cyanophenyl){4-[6-methoxy-7-(3-(1,4-thiazaperhydroin-4-yl)propoxy)quinazolin-4-yl]piperazinyl}corboxamide (4-{7-[3-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))propoxy]-6-methoxyquinazolin-4-yl}piperazinyl)-N-(4-cyanophenyl)carboxamide N-(4-cyanophenyl)[4-(7-ethoxy-6-methoxyquinazolin-4-yl)piperazinyl]carboxamide [4-(7-ethoxy-6-methoxyquinazolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide [4-(7-ethoxy-6-methoxyquinazolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide [4-(7-ethoxy-6-methoxyquinazolin-4-yl)piperazinyl]-N-(4-indol-4-yloxyphenyl) carboxamide [4-(7-ethoxy-6-methoxyquinazolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl) carboxamide N-(4-cyanophenyl)[4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl) piperazinyl]carboxamide [4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide [4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide N-(4-indol-4-yloxyphenyl)[4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl)piperazinyl]carboxamide [4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide N-(4-cyanophenyl)[4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl) piperazinyl]carboxamide [4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl)piperazinyl]-N-[4-(methylethoxy))phenyl]carboxamide [4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide N-(4-indol-4-yloxyphenyl)[4-(6-methoxy-7-prop-2-ynyloxy quinazolin-4-yl)piperazinyl]carboxamide [4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide (4-{6-methoxy-7-[3-(2-methylpiperidyl)propoxy]quinazolin-4-yl}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide (4-{6-methoxy-7-[3-(4-methylpiperidyl)propoxy]quinazolin-4-yl}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide N-(4-cyanophenyl)(4-{6-methoxy-7-[3-(2-methylpiperidyl)propoxy]quinazolin-4-yl}piperazinyl)carboxamide N-(4-cyanophenyl)(4-{6-methoxy-7-[3-(4-methylpiperidyl)propoxy]quinazolin-4-yl}piperazinyl)carboxamide {4-[7-(2-hydroxy-3-piperidylpropoxy-6-methoxyquinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide {4-[7(2-fluoro-3-piperidylpropoxy)-6-methoxyquinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide [4-(6-methoxy-7-{3-[(2-methylpropyl)sulfonyl]propoxy}quinazolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide (4-{6-methoxy-7-[3-(propylsulfonyl)propoxy]quinazolin-4-yl)piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide methyl 4-({4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}carbonylamino)benzoate N-(4-acetylphenyl){4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}carboxamide N-(4-bromophenyl){4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}carboxamide {4-[6-methoxy-7-(3-pyrrolidinylpropoxy)qunazolin-4-yl]piperazinyl}-N-[4-(trifluoromethyl)phenyl]carboxamide {4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}-N-(4-methylphenyl)carboxamide {4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylsulfonyl)phenyl]carboxamide N-(4-fluorophenyl){4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}carboxamide 4-({4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}carbonylamino)benzoic acid 
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
Preparation of Compounds
The compounds may be prepared using methods and procedures as generally described in WO 98/14431 published Sep. 12, 1998, which is incorporated herein by reference. Starting materials may be made or obtained as described therein as well. Leaving groups such as halogen, lower alkoxy, lower alkylthio, lower alkylsulfonyloxy, arylsulfonyloxy, etc, may be utilized when necessary except for the reaction point, followed by deprotection. Suitable amino protective groups are, for example, those described in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons Inc. (1981), etc., such as ethoxycarbonyl, t-butoxycarbonyl, acetyl and benzyl. The protective groups can be introduced and eliminated according to conventional methods used in organic synthetic chemistry [e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons Inc. (1981)].
In such processes, if the defined groups change under the conditions of the working method or are not appropriate for carrying out the method, the desired compound can be obtained by using the methods for introducing and eliminating protective groups which are conventionally used in organic synthetic chemistry [e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons Inc. (1981)], etc. Conversion of functional groups contained in the substituents can be carried out by known methods [e.g., R. C. Larock, Comprehensive Organic Transformations (1989)] in addition to the above-described processes, and some of the active compounds of formula I may be utilized as intermediates for further synthesizing novel derivatives according to formula I.
The intermediates and the desired compounds in the processes described above can be isolated and purified by purification methods conventionally used in organic synthetic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various kinds of chromatography. The intermediates may be subjected to the subsequent reaction without purification.
There may be tautomers for some formula I, and the present invention covers all possible isomers including tautomers and mixtures thereof. Where chiral carbons lend themselves to two different enantiomers, both enantiomers are contemplated as well as procedures for separating the two enantiomers.
In the case where a salt of a compound of formula I is desired and the compound is produced in the form of the desired salt, it can be subjected to purification as such. In the case where a compound of formula I is produced in the free state and its salt is desired, the compound of formula I is dissolved or suspended in a suitable organic solvent, followed by addition of an acid or a base to form a salt.
The following non-limiting reaction Schemes I and II illustrate preferred embodiments of the invention with respect to making compounds according to the invention. 
This synthesis of a tert-butyl-4-[6-methoxy-7-(phenyhnethoxy)quinazolin-4-yl]-piperazine carboxylate compound, provides an intermediate that can be utilized in the synthesis of various compounds (the scheme can be adapted to produce bicyclic position isomers) as described above for formula I. The vanillic acid is benzylated, followed by nitration with fuming nitric acid at about 100° C. The nitro functionality is reduced with a reducing agent such as tin chloride, and the like, followed by cyclization with a base such as formamide at elevated temperature, preferably in the range 100 to 200° C. to afford quinazolinone. The synthesis of 4-Cl-quinazoline is effected by treating quinazolinone with halogenating reagents such as thionyl chloride, oxalyl chloride and phosphorous oxychloride in presence of solvent such as toluene, or carbon tetrachloride. This intermediate is obtained by treating 4-Cl-quinazoline with Boc-piperazine in an appropriate solvent, such as isopropanol, acetonitrile, or THF at room or reflux temperature for 1-6 h in presence of base triethylamine or pyridine. 
This illustrated Scheme III provides the synthesis of various substituted urea intermediates from the intermediate obtained in Scheme I, or by other procedures. The intermediate form Scheme I (or its bicyclic position isomer) is debenzylated under hydrogenation conditions followed by alkylation with various substituted allyl halides. Deprotection of Boc group is effected by trifluoroacetic acid followed by treatment with various isocyanates to afford the final urea compounds. In cases where the isocyanates are not commercially available, the piperazine intermediate may be treated with phosgene to give a carbamoyl chloride intermediate followed by reaction with various substituted anilines. The piperazine intermediate can also be treated with p-nitrophenyl chloroformate to afford a nitrophenyl carbamate intermediate that can be treated with various anilines to afford the desired ureas. If the urea compound has a terminal NH2 group (or one or more of the hydrogen atoms on this amino group is replaced by a displaceable substituent), then this compound may be utilized an intermediate compound with which to produce a urea compound terminated with a —NH-phenyl-R1 groups. Alternatively, if a different R1 group is desired on the phenyl group, a replaceable para position leaving group phenyl substituent may be displaced after coupling to provide the particular R1 substituent as described for formula I, above.
Such procedures for producing the claimed compounds are merely an illustration of a preferred aspect of the invention. Other procedures and adaptations will be apparent to one of ordinary skill in the art upon views these reaction schemes and the structures of the compounds according to the invention. Such procedures are deemed to be within the scope of the present invention.
Also, the compounds of formula I and phannaceutically acceptable salts thereof may exist in the form of adducts with water (hydrates) or various solvents, which are also within the scope of the present invention.
The following non-limiting examples are provided to better illustrate the present invention.